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Silvia G Priori - One of the best experts on this subject based on the ideXlab platform.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:Ion Channel Mutations and Drug-Induced TdP. The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of “forme fruste” of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks Ikr, and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with Ikr blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
Carlo Napolitano - One of the best experts on this subject based on the ideXlab platform.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:Ion Channel Mutations and Drug-Induced TdP. The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of “forme fruste” of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks Ikr, and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with Ikr blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
Gulum Kosova - One of the best experts on this subject based on the ideXlab platform.
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common genetic variant risk score is associated with drug induced QT Prolongation and torsade de pointes risk a pilot study
Circulation, 2017Co-Authors: David G Strauss, Jay W Mason, Raymond L Woosley, Elijah R Behr, Jose Vicente, Lars Johannesen, Ksenia Blinova, Peter Weeke, Dan M Roden, Gulum KosovaAbstract:Background: Drug-Induced QT interval Prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to Drug-Induced QT Prolongation and arrhythmias is not known. Methods: We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject’s Drug-Induced increase in heart rate–corrected QT (QTc) versus drug concentration. Results: The genetic QT score was correlated with Drug-Induced QTc Prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide ( r =0.55; 95% confidence interval, 0.09–0.81; P =0.02), 23% in response to quinidine ( r =0.48; 95% confidence interval, −0.03 to 0.79; P =0.06), and 27% in response to ranolazine ( r =0.52; 95% confidence interval, 0.05–0.80; P =0.03). Furthermore, the genetic QT score was a significant predictor of Drug-Induced torsade de pointes in an independent sample of 216 cases compared with 771 controls ( r 2=12%, P =1×10−7). Conclusions: We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in Drug-Induced QT Prolongation and is a significant predictor of Drug-Induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. Clinical Trial Registration: URL: . Unique identifier: [NCT01873950][1]. # Clinical Perspective {#article-title-34} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01873950&atom=%2Fcirculationaha%2F135%2F14%2F1300.atom
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common genetic variant risk score is associated with drug induced QT Prolongation and torsade de pointes risk a pilot study
Circulation, 2017Co-Authors: David G Strauss, Jay W Mason, Raymond L Woosley, Elijah R Behr, Jose Vicente, Lars Johannesen, Ksenia Blinova, Peter Weeke, Dan M Roden, Gulum KosovaAbstract:Background:Drug-Induced QT interval Prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution...
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common genetic variant risk score is associated with drug induced QT Prolongation and torsade de pointes risk
Circulation, 2017Co-Authors: David G Strauss, Jay W Mason, Raymond L Woosley, Elijah R Behr, Jose Vicente, Lars Johannesen, Ksenia Blinova, Peter Weeke, Dan M Roden, Gulum KosovaAbstract:Background:Drug-Induced QT interval Prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution...
J Peter M D Schwartz - One of the best experts on this subject based on the ideXlab platform.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:Ion Channel Mutations and Drug-Induced TdP. The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of “forme fruste” of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks Ikr, and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with Ikr blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
Arthur M Brown - One of the best experts on this subject based on the ideXlab platform.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of "forme fruste" of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks I(Kr), and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with I(Kr) blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
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evidence for a cardiac ion channel mutation underlying drug induced QT Prolongation and life threatening arrhythmias
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Carlo Napolitano, J Peter M D Schwartz, Arthur M Brown, Elena Ronchetti, Laura Bianchi, M Aldo D Pinnavaia, M Giovanni D Acquaro, Silvia G PrioriAbstract:Ion Channel Mutations and Drug-Induced TdP. The aim of this study was to test the hypothesis that some cases of Drug-Induced arrhythmias depend on genetic predisposition. Excessive Prolongation of the QT interval and life-threatening arrhythmias (torsades de pointes or ventricular fibrillation) may occur in response to a variety of cardiac and noncardiac drugs, with detrimental effects on patient safety and the investments made by the pharmaceutical industry. Moss and Schwartz hypothesized that some Drug-Induced arrhythmias might represent cases of “forme fruste” of the congenital long QT syndrome (LQTS). The availability of molecular screening techniques for LQTS genes allowed us to test this hypothesis. An elderly female patient with documented cardiac arrest related to cisapride, a prokynetic drug that blocks Ikr, and transiently prolonged QT interval underwent mutational analysis of the known LQTS-related genes performed by single-strand conformational polymorphism and DNA sequencing. Double-electrode voltage clamp in Xenopus oocytes as the expression system was used to study the in vitro cellular phenotype caused by the genetic defect in coexpression with the wild-type (WT) gene. Molecular analysis revealed a heterozygous mutation leading to substitution of a highly conserved amino acid in the pore region of KvLQT1. This mutation was present not only in the patient with ventricular fibrillation but also in her two adult asymptomatic sons who have a normal QT interval. In vitro expression of the mutated KvLQT1 protein showed a severe loss of current with a dominant negative effect on the WT-KvLQT1 channel. Our findings demonstrate that some cases of Drug-Induced QT Prolongation may depend on a genetic substrate. Molecular screening may allow identification among family members of gene carriers potentially at risk if treated with Ikr blockers. Evolving technology may lead to rapid screening for mutations of candidate genes that cause Drug-Induced life-threatening arrhythmias and allow early identification of individuals at risk.
